Treatment

Abstract

Inhalable compositions comprising niclosamide, or a pharmaceutically acceptable salt thereof, and polyethylene glycol; aerosols of the compositions; and the pulmonary administrations for use in the treatment of viral infections, for example respiratory viral infections.

1 . An inhalable pharmaceutical composition comprising niclosamide, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a viral infection in a subject, wherein the niclosamide, or a pharmaceutically acceptable salt thereof, is administered to the subject by inhalation. 
     
     
         2 . The composition for the use of  claim 1 , wherein the pharmaceutical composition is in the form of a powder, a suspension or a solution comprising niclosamide, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The composition for the use of  claim 1 , wherein the pharmaceutical composition is in the form of a solution or suspension comprising niclosamide, or a pharmaceutically acceptable salt thereof, preferably a liquid solution or liquid suspension. 
     
     
         4 . The composition for the use of  claim 3 , wherein the solution or suspension comprises niclosamide, or a pharmaceutically acceptable salt thereof, and polyethylene glycol (PEG). 
     
     
         5 . The composition for the use of  claim 4 , wherein the PEG has an average molecular weight of less than about 600. 
     
     
         6 . The composition for the use of  claim 4  or  claim 5 , wherein the PEG has an average molecular weight of from about 150 to about 600, for example an average molecular weight of about 200 or about 400. 
     
     
         7 . The composition for the use of any one of  claims 4  to  6 , wherein the PEG is present in an amount of at least 25% by weight of the composition, for example, wherein the PEG is present in an amount of at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% by weight of the composition. 
     
     
         8 . The composition for the use of any one of  claims 4  to  6 , wherein the PEG is present in an amount of from about 40% to about 98% by weight of the composition, for example from about 70% to about 96% by weight of the composition. 
     
     
         9 . The composition for the use of any one of  claims 3  to  8 , wherein the solution or suspension further comprises a solvent (e.g. a glycol such as propylene glycol). 
     
     
         10 . The composition of any one of  claims 3  to  9 , wherein the composition is in the form of a suspension comprising niclosamide, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The composition for the use of any one of  claims 3  to  9 , wherein the composition is in the form of a solution comprising niclosamide, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The composition for the use of any one of  claims 3  to  11 , wherein the composition is administered to the subject in the form of an aerosol of the solution or suspension comprising niclosamide, or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The composition for the use of any one of  claims 1  to  12 , wherein the composition comprises niclosamide in the free-acid form. 
     
     
         14 . The composition for the use of any one of  claims 1  to  12 , wherein the composition comprises a pharmaceutically acceptable salt of niclosamide. 
     
     
         15 . The composition for the use of any one of  claims 1  to  12 , wherein the composition comprises niclosamide ethanolamine. 
     
     
         16 . The composition for the use of any one of  claims 1  to  15 , wherein the niclosamide or a pharmaceutically acceptable salt thereof is present in the composition in an amount of from about 0.1% to about 10% by weight of the composition, for example about 5% by weight of the composition. 
     
     
         17 . The composition for the use of  claim 1 , wherein the composition is a solution comprising from about 1% to about 10% by weight niclosamide ethanolamine and PEG, wherein the PEG has an average molecular weight of less than 600. 
     
     
         18 . The composition for the use of  claim 1 , wherein the composition is a solution comprising from about 4.5% to about 6.5% by weight niclosamide ethanolamine and about 93.5% to about 95.5% by weight PEG 400. 
     
     
         19 . The composition for the use of  claim 17  or  claim 18 , wherein the solution is administered to the subject in the form of an aerosol of the solution. 
     
     
         20 . The composition for the use of any one of  claims 1  to  19 , wherein the composition further comprises a taste-masking agent. 
     
     
         21 . The composition for the use of  claim 20 , wherein the taste-masking agent is selected from a sugar (e.g. sucrose, dextrose, or lactose), an amino acid or amino acid derivative (e.g. arginine, lysine, or monosodium glutamate), an oil (e.g. a natural oil, or plant extract), a sweetener (e.g. sucrose, dextrose, aspartame, acesulfame-K, sucralose or saccharin), an organic acid (e.g. citric acid or aspartic acid), and maltodextrin. 
     
     
         22 . The composition for the use of any one of  claims 1  to  21 , wherein the composition is a non-aqueous composition, for example a composition containing less than 2% by weight water, preferably less than 0.1% by weight water, more preferably wherein the composition is anhydrous. 
     
     
         23 . A method for preventing or treating a viral infection is a subject, the method comprising administering to the subject by inhalation an effective amount of an inhalable pharmaceutical composition comprising niclosamide, or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method of any  claim 23 , wherein the composition is as defined in any one of  claims 2  to  22 . 
     
     
         25 . The composition for use, or method of any one of  claims 1  to  24 , wherein the niclosamide, or a pharmaceutically acceptable salt thereof, is administered to the subject in a daily dose of from about 1 mg to about 3000 mg based on the weight of niclosamide (for example, from about 400 mg to about 2000 mg based on the weight of the niclosamide). 
     
     
         26 . The composition for use, or method of any one of  claims 1  to  25 , wherein the niclosamide, or a pharmaceutically acceptable salt thereof, is administered to the subject in a unit dosage of from about 10 mg to about 1000 mg based on the weight of niclosamide (for example from about 100 mg to about 600 mg, preferably about 150 mg to about 500 mg, based on the weight of niclosamide). 
     
     
         27 . The composition for use, or method of any one of  claims 1  to  26 , wherein the composition is administered by inhalation intraorally and/or intranasally, preferably wherein the niclosamide or solution is administered by inhalation intraorally. 
     
     
         28 . The composition for use, or method of any one of  claims 1  to  26 , wherein the composition is administered intranasally. 
     
     
         29 . The composition for use, or method of any one of  claims 1  to  28 , wherein the composition is administered to the subject one to five times per day, for example from 1 to 4 times per day. 
     
     
         30 . The composition for use, or method of any one of  claims 1  to  29 , wherein the subject is treated with an antitussive agent prior to or concurrently with the inhaled niclosamide, or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The composition for use, or method of  claim 30 , wherein the antitussive agent is selected from codeine, dextromethorphan, hydrocodone, methadone, butorphanol, benzonatate, ethylmorphine, oxeladin, pipazethate, pholcodine, noscapine, butamirate and a local anaesthetic. 
     
     
         32 . The composition for use, or method of  claim 30 , wherein the antitussive agent is a local anaesthetic, preferably lidocaine. 
     
     
         33 . The composition for use, or method of any one of  claims 30  to  32 , wherein antitussive agent is administered to the subject prior to the inhaled niclosamide. 
     
     
         34 . The composition for use, or method of any one of  claims 1  to  33 , wherein the viral infection is a pulmonary viral infection. 
     
     
         35 . The composition for use, or method of any one of  claims 1  to  34 , wherein the viral infection is caused by or associated with a virus selected from respiratory syncytial virus, influenza virus, parainfluenza virus, human metapneumovirus, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), a human rhinovirus (HRVs) and human adenovirus (HAdV). 
     
     
         36 . The composition for use, or method of any one of  claims 1  to  34 , wherein the viral infection is caused by or associated with a Pneumoviridae virus, for example a Human respiratory syncytial virus (HRSV) (e.g. HRSV-A2, HRSV-B1 or HRSV-S2). 
     
     
         37 . The composition for use, or method of any one of  claims 1  to  34 , wherein the viral infection is caused by or associated with a Coronaviridae virus. 
     
     
         38 . The composition for use, or method of  claim 35 , wherein the virus is selected from Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus. 
     
     
         39 . The composition for use, or method of  claim 36 , wherein the virus is a Betacoronavirus. 
     
     
         40 . The composition for use, or method of  claim 37 , wherein the virus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), HCoV-229E, HCoV-NL63, HCoV-OC43 and HKU1. 
     
     
         41 . The composition for use, or method of any one of  claims 1  to  33 , wherein the viral infection is caused by or associated with SARS-CoV-2. 
     
     
         42 . The composition for use, or method of any one of  claims 1  to  33 , wherein the viral infection is COVID-19, optionally wherein the viral infection is moderate or mild COVID-19. 
     
     
         43 . The composition for use, or method of any one of  claims 1  to  33 , wherein the viral infection is caused by or associated with influenza virus. 
     
     
         44 . An aerosol of a solution comprising niclosamide, or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The aerosol of  claim 44 , wherein the solution comprises niclosamide, or a pharmaceutically acceptable salt thereof, and polyethylene glycol (PEG). 
     
     
         46 . The aerosol according to  claim 44  or  claim 45 , wherein the PEG has an average molecular weight of less than about 600. 
     
     
         47 . The aerosol of any one of  claim 45  or  claim 46 , wherein the PEG has an average molecular weight of from about 150 to about 600, for example an average molecular weight of about 200 or about 400. 
     
     
         48 . The aerosol of any one of  claims 45  to  47 , wherein the PEG is present in an amount of at least 25% by weight of the solution, for example, wherein the PEG is present in an amount of at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% by weight of the solution. 
     
     
         49 . The aerosol of any one of  claims 45  to  48 , wherein the PEG is present in an amount of from about 40% to about 98% by weight of the solution. 
     
     
         50 . The aerosol of any one of  claims 44  to  49 , wherein the solution comprises a solution of niclosamide in the free-acid form. 
     
     
         51 . The aerosol of any one of  claims 44  to  49 , wherein the solution comprises a solution of a pharmaceutically acceptable salt of niclosamide. 
     
     
         52 . The aerosol of any one of  claims 44  to  49 , wherein the solution comprises a solution of niclosamide ethanolamine. 
     
     
         53 . The aerosol of any one of  claims 44  to  52 , wherein the niclosamide or a pharmaceutically acceptable salt thereof is present in the solution in an amount of from 0.1% to 10% by weight of the solution, for example about 5% by weight of the solution. 
     
     
         54 . The aerosol of  claim 44 , wherein the composition is a solution comprising from about 4.5% to about 6.5% by weight niclosamide ethanolamine and about 93.5% to about 95.5% by weight PEG 400. 
     
     
         55 . The aerosol of any one of  claims 44  to  54 , wherein the solution further comprises a taste-masking agent. 
     
     
         56 . The aerosol of  claim 55 , wherein the taste-masking agent is selected from a sugar (e.g. sucrose, dextrose, or lactose), a amino acid or amino acid derivative (e.g. arginine, lysine, or monosodium glutamate), an oil (e.g. a natural oil, or plant extract), a sweetener (e.g. aspartame, acesulfame-K, sucralose or saccharin), an organic acid (e.g. citric acid or aspartic acid), and maltodextrin. 
     
     
         57 . The aerosol of any one of  claims 44  to  56 , wherein the solution further comprises a solvent (e.g. e.g. a glycol such as propylene glycol). 
     
     
         58 . The aerosol of any one of  claims 44  to  56 , wherein the solution is a non-aqueous solution, for example a solution containing less than 2% by weight water, preferably less than 0.1% by weight water, more preferably wherein the solution is anhydrous. 
     
     
         59 . The aerosol of any one of  claims 44  to  58 , wherein the mass median diameter (MMD) of the aerosol is less than about 5 μm. 
     
     
         60 . The aerosol of any one of  claims 44  to  58 , wherein the mass median diameter (MMD) of the aerosol is less than about 2 μm. 
     
     
         61 . The aerosol of any one of  claims 44  to  58 , wherein the mass median diameter (MMD) of the aerosol is from about 0.5 μm to about 5.5 μm, preferably from about 1 μm to about 5 μm. 
     
     
         62 . The aerosol of any one of  claims 44  to  58 , wherein the mass median diameter (MMD) of the aerosol is less than about 500 μm, preferably less than about 200 μm. 
     
     
         63 . The aerosol of any one of  claims 44  to  58 , wherein the mass median diameter (MMD) of the aerosol is from about 5 to about 150 μm, preferably from about 20 to about 100 μm. 
     
     
         64 . An aerosol according to any one of  claims 44  to  63 , for use in the prevention or treatment of a viral infection in a subject, wherein the aerosol is administered to the subject by inhalation. 
     
     
         65 . An aerosol according to any one of  claims 44  to  63 , for use in the prevention or treatment of a viral infection in a subject, wherein the aerosol is administered to the subject intranasally. 
     
     
         66 . An inhalable unit dosage comprising a solution of niclosamide, or a pharmaceutically acceptable salt thereof, and PEG, wherein niclosamide is present in an amount of from 1 mg to 600 mg based on the weight of niclosamide, for example from about 150 mg to about 500 mg, based on the weight of niclosamide. 
     
     
         67 . An inhalable unit dosage comprising a solution of niclosamide ethanolamine and PEG, wherein niclosamide ethanolamine is present in an amount of from 2 mg to 600 mg, for example from about 150 mg to about 500 mg. 
     
     
         68 . The inhalable unit dosage according to  claim 66  or  67 , wherein the unit dosage form is present in a container, for example a vial, blister pack, bottle, syringe or drug reservoir within an inhaler device (e.g. a nebulizer). 
     
     
         69 . The inhalable unit dosage according to any one of  claims 66  to  68 , wherein the solution is a non-aqueous solution, for example a solution containing less than 2% by weight water, preferably less than 0.1% by weight water, more preferably wherein the solution is anhydrous. 
     
     
         70 . A system comprising a container comprising a solution of niclosamide, or a pharmaceutically acceptable salt thereof, and polyethylene glycol (PEG); and an inhaler device and/or an intranasal delivery device. 
     
     
         71 . A kit comprising a container comprising a solution of niclosamide, or a pharmaceutically acceptable salt thereof, and polyethylene glycol (PEG); and an inhaler device and/or an intranasal delivery device. 
     
     
         72 . The system or kit according to  claim 70  or  claim 71 , wherein the inhaler device or the intranasal delivery device is adapted to aerosolize the solution. 
     
     
         73 . The system or kit according to  claim 72 , wherein the inhaler device or the or an intranasal delivery device is adapted to deliver the aerosolized solution intranasally or intraorally to a subject. 
     
     
         74 . The system or kit according to any one of  claims 70  to  73 , wherein the inhaler device is selected from a jet nebulizer, a vibrating mesh nebulizer, an ultrasonic nebulizer or a pressurised metered dose inhaler (pMDI). 
     
     
         75 . An inhalable solution comprising from about 1% to 10% by weight niclosamide ethanolamine and PEG, wherein the PEG has an average molecular weight of less than 600; and optionally a taste-masking agent. 
     
     
         76 . An inhalable solution according to  claim 75 , comprising from about 4.5% to about 6% by weight niclosamide ethanolamine; about 90% to 95.5% PEG 400 and optionally a taste-masking agent. 
     
     
         77 . An inhalable solution according to  claim 75 , comprising from about 4.5% to about 6% by weight niclosamide ethanolamine; about 90% to 95.5% PEG 200 and optionally a taste-masking agent. 
     
     
         78 . The inhalable solution according to any one of  claims 75  to  77 , wherein the solution is a non-aqueous solution, for example a solution containing less than 2% by weight water, preferably less than 0.1% by weight water, more preferably wherein the solution is anhydrous. 
     
     
         79 . The composition for use or method according to any one of  claims 1  to  78 , wherein the subject is hospitalized. 
     
     
         80 . The composition for use or method according to any one of  claims 1  to  79 , wherein the composition is for preventing, or reducing the likelihood of, progression of the disease, e.g. from mild to moderate or from moderate to severe COVID-19. 
     
     
         81 . The composition for use or method according to any one of  claims 1  to  80 , wherein the composition is administered prophylactically. 
     
     
         82 . The composition for use or method according to  claim 81 , wherein the composition is prophylactically administered to a subject who has been, or is suspected as having been, exposed to a person who is diagnosed as being infected with a viral infection. 
     
     
         83 . The composition for use or method according to  claim 82 , wherein the viral infection is SARS-CoV-2. 
     
     
         84 . The composition for use or method according to  claim 81 , wherein the composition is prophylactically administered to a non-infected subject who is at a higher risk from COVID-19. 
     
     
         85 . The composition for use or method according to any one of  claims 81  to  84 , wherein the prophylactic administration is for:
 reducing the risk of the subject contracting symptomatic or non-symptomatic COVID-19 infection; 
 reducing the risk of mortality from COVID-19; 
 reducing the severity of symptoms of COVID-19; and/or 
 reducing the risk of the subject contracting moderate or severe COVID-19. 
 
     
     
         86 . The composition for use or method according to any one of  claims 81  to  84 , wherein the prophylactic administration is for:
 reducing the risk of the subject contracting a secondary infection (e.g. a secondary bacterial infection 
 reducing the risk of mortality from a secondary infection; and/or 
 reducing the severity of a secondary infection. 
 
     
     
         87 . The composition for use or method according to  claim 84 , wherein the subject has an existing condition or disease, such as: such as diabetes, cancer, heart disease, hypertension, cerebrovascular disease, SCID, sickle cell disease, thalassemia, pulmonary fibrosis, interstitial lung disease, chronic lung disease such as COPD, asthma and cystic fibrosis, emphysema, bronchitis, chronic kidney disease, chronic liver disease, hepatitis, autoimmune disease, a condition affecting the brain or nerves, a muscle wasting condition, or a severe or profound learning disability. 
     
     
         88 . The composition for use or method according to  claim 84 , wherein the subject is selected from: subjects who have had a body tissue (e.g. an organ) transplant; subjects who have had an organ (e.g. spleen) removed; subjects receiving (or who have received) chemotherapy, immunotherapy, antibody therapy or radiotherapy; subjects receiving (or who have received) cancer treatment; subjects receiving (or who have received) protein kinase inhibitors or PARP inhibitors; subjects who have had a blood, bone marrow or stem cell transplant; subjects taking immunosuppressants; subjects with HIV or AIDS; and subjects on haemodialysis. 
     
     
         89 . The composition for use or method according to any preceding claim, wherein the composition is for use in the treatment of a viral infection in an asymptomatic subject, optionally wherein the viral infection is SARS-CoV-2. 
     
     
         90 . The composition for use or method according to any preceding claim, wherein the treatment is for:
 reducing or eliminating the viral load in the subject;   accelerating seroconversion in the subject;   reducing inter-subject transmission of the viral;   reducing viral shedding;   preventing or reducing the risk of the subject developing symptoms; and/or   preventing or reducing the risk of progression of disease.   
     
     
         91 . The composition for use or method according to any preceding claim, wherein the composition is administered intranasally.